It is well established in medical literature that treatments currently available for pain have limitations. Opioid drugs cause tolerance, dependence and side effects sufficiently serious to prompt recent action by the FDA to further restrict the drugs. Newly approved treatments, like the calcium channel alpha-2-delta ligands gabapentin and pregabalin and the serotonin and norepinephrine reuptake inhibitors milnacipran and duloxetine, require high doses to show nominal effectiveness, have a high dropout rate and carry many side effects.
This invention is a novel approach for the treatment of pain. It is directed to the treatment of neuropathic and nociceptive pain with an allodynic component. One component of the combination is directed to reducing neuropathic pain and the allodynic component associated with nociceptive pain and the other component address nociceptive pain. Specific combination of drugs and the dosage needed to create that effect is the subject of the instant invention.
The unifying theory explaining neuropathic pain is the understanding that TLR4 are activated endogenously and trigger a pro-inflammatory cascade. That cascade is interrupted and in most cases eliminated by treatment using the systemic administration of an opioid/TLR4 antagonist, particularly naltrexone, or a pharmaceutically acceptable salt, thereof.
A cyclooxygenase (COX) inhibitor particularly ibuprofen, or a pharmaceutically acceptable salt thereof, enhances the pain relief action of the opioid/TLR4 antagonist naltrexone. A specific synergistic dose range of the combination is herein presented.
In a dose finding study the combination of the opioid/TLR4 antagonist, naltrexone and the cyclooxygenase (COX) inhibitor ibuprofen, acted synergistically, whether administered separately, one right after the other, or administered in combination.
Various μ-opioid receptor ligands have been tested and were found to also possess action as agonists or antagonists of Toll-like receptor 4 (TLR4). Toll-like receptors, found in the glia, are a class of receptors that play a key role in the innate immune system. They recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. Opioid agonists such as morphine act as TLR4 agonists, while opioid antagonists such as naloxone and naltrexone were found to be TLR4 antagonists. Activation of TLR4 by opioid agonists such as morphine leads to downstream release of inflammatory modulators including TNF-α and interleukin-1. Constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time and to be involved in both the development of tolerance to opioid analgesic drugs and in the emergence of side effects such as hyperalgesia and allodynia which can become problems following extended use of opioid drugs.
Accordingly, the instant invention relates to μ-opioid receptor ligand as ligands of TLR4 as well and contemplates that allodynia is caused by activation of TLR4. Blockage of TLR4 accordingly will eliminate allodynia.
The best known opioid receptor antagonists are naloxone and naltrexone. Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. A dose of 50-300 mg once daily is recommended for most patients. Naloxone is an opioid inverse agonist: it is a drug used to counter the effects of opiate overdose.
Low dose naltrexone describes the off label use of naltrexone at doses less than 10 mg per day for indications other than chemical dependency or intoxication.
It has been suggested in the literature that low dose naltrexone exerts the opposite effect of naltrexone in full dose. While the full dose naltrexone blocks the opiate system, the low dose naltrexone promotes the production of endorphins by the mechanism of up regulation caused by partial opiate receptor blockage. The beneficial effect of naltrexone was attributed to the increase in endorphins. The beneficial effect of low dose naltrexone can be further explained by its antagonism of TLR4.
Other opioid receptor antagonists used in clinical or scientific practice which also can be used for the treatment of pain include but are not limited to the following: naloxone, nalmefene, norbinaltorphimine, nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole, amentoflavone, naltriben, norbinaltorphimine, and the naltrexone metabolite 6-β-naltrexol.
Our understanding of pathological pain has primarily revolved around neuronal mechanisms. However, neighboring glia, were TLL4 reside, including astrocytes and microglia; have recently been recognized as powerful modulators of pain.
Studies show that TLRs can be activated not only by well-known “non-self” molecular signals but also by endogenous signals (IL-1β, TNFα, IL-6 and NO) produced during chronic neuropathic pain states. Fibronectin, an endogenous TLR4 ligand that is produced in response to tissue injury, leads to an up regulation of the purinoceptor P2X4, which is expressed exclusively on microglia.
Several opioid antagonist drugs were found to act as antagonists for TLR4, including naloxone and naltrexone. However it was found that not only the “normal” (−) enantiomers, but also the “unnatural” (+) enantiomers of these drugs acted as TLR4 antagonists. The unnatural enantiomers of the opioid antagonists, (+)-naltrexone and (+)-naloxone, dextro-naltrexone and dextro-naloxone, have been discovered to act as selective antagonists of TLR4. Since (+)-naloxone and (+)-naltrexone lack affinity for opioid receptors, they do not block the effects of opioid analgesic drugs, and so can be used to counteract the TLR4-mediated side effects of opioid agonists without affecting analgesia. (+)-Naloxone was also found to be neuroprotective, and both (+)-naloxone and (+)-naltrexone are effective in their own right at treating symptoms of neuropathic pain in animal models.
Most nonsteroidal anti-inflammatory drugs (NSAIDs) act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is competitively reversible (albeit at varying degrees of reversibility). COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid. Prostaglandins act as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane (1927-2004), who received a Nobel Prize for his work. NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) it is used primarily for fever, pain, dysmenorrhea and inflammatory diseases such as rheumatoid arthritis; it is also used for pericarditis. Ibuprofen is a ‘core’ medicine in the World Health Organization's Model List of Essential Medicines necessary to meet the minimum medical needs of a basic healthcare system.
Ibuprofen enhances the pain treatment effect of naltrexone by inhibiting the enzyme cyclooxygenase (COX), which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins, which are mediators of pain, inflammation, and fever.
Nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly localized pain. Examples include sprains and broken bones.
Allodynia is a clinical feature of many painful conditions, such as back pain, chronic pain, neuropathic pain, diabetic neuropathic pain, trigeminal neuralgia pain, phantom limb pain, complex regional pain syndrome pain, acute herpetic pain, post herpetic pain, causalgia pain, idiopathic pain, inflammatory pain, cancer pain, postoperative pain, fibromyalgia pain, headache pain, migraine pain, allodynia pain, vulvodynia pain, interstitial cystitis pain, irritable bowel syndrome (IBS), arthritic joint pain and tendinitis. It becomes apparent that allodynia plays a role in every kind of pain.
The unifying theory of allodynia, or “memory pain”, as allodynia may be described in lay terms, is the understanding that TLR4 are activated endogenously and trigger a pro-inflammatory cascade. That cascade is interrupted by the opioid/TLR4 antagonist drugs as claimed by the instant invention. Additionally, TLR4 antagonism can play a role in improving nociceptive pain as well by affecting the allodynic component of nociceptive pain.
Based upon this, the instant invention first teaches the use of an opioid/TLR4 antagonist, particularly naltrexone for its antagonism of the TLR4 and blocking release of inflammatory modulators. Secondly, the invention teaches use of a cyclooxygenase inhibitor, particularly ibuprofen, for its action on nociception and its anti-inflammatory action. The invention teaches that the combination is synergy as far as the effect on pain treatment.
The invention contemplates several forms of opioid antagonist selected from a group consisting of naltrexone, naloxone, nalmefene, norbinaltorphimine, nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole, amentoflavone, naltriben, norbinaltorphimine, and metabolite 6-β-naltrexol and metabolites and pro drugs thereof, including all enantiomeric and epimeric forms as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
Nonsteroidal anti-inflammatory drug can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action.
The invention contemplates several forms of NSAID's selected from groups consisting of Salicylates: Aspirin Diflunisal, Salsalate. Propionic acid derivatives: Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen. Acetic acid derivatives: Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, iclofenac, Nabumetone. Enolic acid (Oxicam) derivatives: Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam. Fenamic acid derivatives: Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid. Selective COX-2 inhibitors: Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, Firocoxib, Sulphonanilides, Nimesulide, LOX (lipooxygenase) & COX 5-LOX/COX inhibitor: Licofelone, Lysine, clonixinate. Natural: Hyperforin, Figwort, Calcitriol (Vitamin D).